The present invention is generally in the area of medical treatments, and specifically relates to an method for making a non-immunogenic cartilage and bone preparation and use thereof as a bulking agent.
Vesicouretal reflux is a condition wherein there is an abnormal development of the ureteral bud as it enters the bladder during embryologic development. The shortened course of the ureter through the bladder musculature decreases the ureteral resistance and allows for urine to reflux from the bladder reservoir back up into the ureter and into the kidney. With this condition, bacteria which may occasionally be present in the bladder through retrograde urethral transport, can reach the kidneys and cause recurrent pyelonephritis. In addition, the constant back pressure of the urine into the calyces and renal pyramids results in mechanical damage to the renal parenchyma. If untreated, urinary vesicoureteral reflux can cause loss of renal parenchyma, and in some instances, renal failure, as reviewed by Atala and Casale, Infections in Urology 39-43 (March/April 1990). In 1960, 70% of the patients with renal failure were described as having vesicoureteral reflux as the primary etiology. With the advent of new diagnostic and treatment modalities, patients with vesicoureteral reflux now account for less than 1% of the renal failure population.
The initial management of vesicoureteral reflux usually consists of suppressive antibiotics in anticipation of spontaneous resolution, as described by Atala, et al., "Sonography with sonicated albumin in the detection of vesicoureteral reflux" J. Urol. 150:756-758 (1993). Depending on the severity of reflux, 20 to 60 percent of patients may ultimately undergo surgical treatment, as reported by Klagsbrun, M. "Large scale preparation of chondrocytes" Methods in Enzymology 58:560 (1979); O'Donnell and Puri, "Treatment of vesicoureteic reflux by endoscopic injection of Teflon" Brit. Med. J. 289: 7 (1984). Although open surgical procedures for the correction of reflux have excellent results in the hands of experienced surgeons, it is associated with a well recognized morbidity, including pain and immobilization of a lower abdominal incision, bladder spasms, hematuria, and post-operative voiding frequency in some children.
The endoscopic treatment of vesicoureteral reflux was first introduced in 1981 when Polytetrafluoroethylene (Teflon) was injected in the subureteral region of a patient, as reported by Matouschek, E.: Die Behandlung des vesikorenalen Refluxes durch transueterale Einspritzung von polytetrafluoroethylenepaste. Urologe, 20:263 (1981). In an effort to avoid open surgical intervention, widespread interest in the endoscopic treatment of reflux was initiated by O'Donnell and Puri's clinical experience with Polytetrafluoroethylene paste in 1984, (Atala and Casale "Management of primary vesicoureteral reflux" Infections in Urol. 2:39 (1990)). Soon thereafter, a controversy regarding the use of polytetrafluoroethylene paste ensued. Particle migration to distant organs raised concerns regarding the use of polytetrafluoroethylene paste, as reported by Malizia, et al., "Migration and granulomatous reaction after periurethral injection of polyef (polytetrafluoroethylene)" JAMA, 251:3277 (1984); Claes, et al., "Pulmonary migration following periurethral polytetrafluoroethylene injection for urinary incontinence" J. Urol. 142:821 (1989); Vorstman, et al., "Polytetraflouroethylene injection for urinary incontinence in children" J. Urol. 133:248 (1985); Mittleman, et al., "Pulmonary polytetrafluoroethylene granulomas following periurethral polytetrafluoroethylene injection for urinary incontinence" Arch. Path. Lab. Med. 107:611 (1983); Ferro, et al., "Periurethral granuloma: Unusual complications of Teflon periurethral injection" Urology 31:422 (1988); Rames, et al., "Migration of polystef paste to the lung and brain following intravesical injection for the correction of reflux" Ped. Surg. Int. 6:239 (1991).
Bovine dermal collagen preparations have been used to treat reflux endoscopically, as reported by Leonard, et al., "Endoscopic injection of glutaraldehyde cross-linked bovine dermal collagen for correction of vesicoureteral reflux" J. Urol. 145:115 (1991). However, only 58.5% of the patients were cured at one year follow-up. The collagen implant volume decreases with time, which results in a high percentage of recurrence of reflux. The high rate of retreatment necessary due to implant volume loss has limited the usefulness of collagen, as discussed in "Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children" Report of the International Reflux Study Committee. J. Urol, 125:277 (1981). The ideal implant material should be non-migratory, non-antigenic, able to be delivered endoscopically, and should conserve its volume.
A paste consisting of textured microparticles of silicone, suspended in a hydrogel, has been injected subureterally to correct reflux with an initial success rate of 91%, as reported by Buckley, et al., "Endoscopic correction of vesicoureteric reflux with injectable microparticulate silicone" Abstract 573 presented at 87th Annual Meeting, AUA, May 10-14, 1993, Washington DC. Although problems have been encountered with the silicone gel-filled prostheses which have the potential to rupture or leak, the solid silicone prostheses have been mostly problem-free. Recently however, concerns have also been raised regarding the non-gel-filled prostheses. Barrett et al. "Particle shedding and migration from silicone genitourinary prosthetic devices" J. Urol. 146:319-322 (1991), showed silicone particles from 18 of 25 urologic periprosthetic specimens, and in all lymph nodes examined. Foreign body granulomas were identified in 29 specimens. Lymphadenopathy and lymphadenitis have occurred after silicone prosthesis implantation (Paplanus and Payne "Axillary lymphadenopathy 17 years after digital silicone implants: study with x-ray microanalysis" J. Hand. Surg. 13:399 (1988); Endo, et al., "Silicone and rheumatic diseases" Sem. Arth. Rheum. 17:112 (1987)). Silicone particles have been found in the enlarged nodes of patients with malignant lymphoma (Digby "Malignant lymphoma with intranodal silicone rubber particles following metacarpophalangeal joint replacements" Hand 14:326 (1982); Benjamin, et al., "Silicone lympadenopathy: a report of two cases, one with concomitant malignant lymphoma" Diaan. Histopath. 5:133 (1982)). The autoimmune disorder human adjuvant disease, is associated with silicone implantation (Sergott, et al., "Human adjuvant disease possible autoimmune disease after silicone implantation: a review of the literature, case studies, and speculation for the future" Plast. Reconstr. Surg. 78:104 (1986)). Long-term longitudinal studies of patients with silicone prostheses are needed to define the associated risk.
Other materials for the endoscopic treatment of reflux, including a detachable balloon system (Atala et al., "Endoscopic treatment of vesicoureteral reflux with a self-detachable balloon system", J. Urol. 148:724 (1992)) and Bioglass (Walker, et al., "Injectable bioglass as a potential substitute for injectable polytetrafluoroethylene" J. Urol. 148:645 (1992)) are currently under investigation and have not been used in a clinical setting.
Laparoscopic correction of reflux has been attempted in both an animal model (Atala, et al., "Laparoscopic correction of vesicouretal reflux" J. Urol. 150:748-751 (1993)) and humans (Atala, "Laparoscopic treatment of vesicoureteral reflux" Dial Ped Urol 14:212 (1993)) and is technically feasible. However, at least two surgeons with laparoscopic expertise are needed, the length of the procedure is longer than with open surgery, and the cost is higher due to both increased operative time and the expense of the disposable laparoscopic equipment.
The advantages of the endoscopic treatment for reflux cannot be overlooked. The method is simple, can be completed in less than 15 minutes as an outpatient procedure, has a low morbidity and a success rate of more than 85 percent, as reported by Giss, et al., "Multicenter survey of endoscopic treatment of vesicoureteral reflux in children" Eur. Urol. 17:328 (1990). The ideal substance for the endoscopic treatment of reflux should be injectable, non-antigenic, non-migratory, volume stable, and safe for human use.
Urinary incontinence.
Urinary Incontinence is the most common and the most intractable of all GU maladies. Urinary incontinence, or the inability to retain urine and not void urine involuntarily, is dependent on the interaction of two sets of muscles. One is the detrusor muscle, a complex of longitudinal fibers forming the external muscular coating of the bladder. The detrusor is activated by parasympathetic nerves. The second muscle is the smooth/striated muscle of the bladder sphincter. The act of voiding requires the sphincter muscle be voluntarily relaxed at the same time that the detrusor muscle of the bladder contracts. As a person ages, his ability to voluntarily control the sphincter muscle is lost in the same way that general muscle tone deteriorates with age. This can also occur when a radical event such as paraplegia "disconnects" the parasympathetic nervous system causing a loss of sphincter control. In different patients, urinary incontinence exhibits different levels of severity and is classified accordingly.
The most common incontinence, particular in the elderly, is urge incontinence. This type of incontinence is characterized by an extremely brief warning following by immediate urination. This type of incontinence is caused by a hyperactive detrusor and is usually treated with "toilet training" or medication. Reflex incontinence, on the other hand, exhibits no warning and is usually the result of an impairment of the parasympathetic nerve system such as a spinal cord injury.
Stress incontinence is most common in elderly women but can be found in women of any age. It is also commonly seen in pregnant women. This type of incontinence accounts for over half of the total number of cases. It is also found in men but at a lower incidence. Stress incontinence is characterized by urine leaking under conditions of stress such as sneezing, laughing or physical effort. There are five recognized categories of severity of stress incontinence, designated as types as 0, 1, 2a, 2b, and 3. Type 3 is the most severe and requires a diagnosis of intrinsic Sphincter Deficiency or ISD (Contemporary Urology, March 1993). There are many popular treatments including weight loss, exercise, medication and in more extreme cases, surgical intervention. The two most common surgical procedures involve either elevating the bladder neck to counteract leakage or constructing a lining from the patient's own body tissue or a prosthetic material such as PTFE to put pressure on the urethra. Another option is to use prosthetic devices such as artificial sphincters to external devices such as intravaginal balloons or penile clamps. For treatment of type 3 stress incontinence, there has been a recent trend toward injection of Teflon.TM. or collagen paste around the sphincter muscle in order to "beef up" the area and improve muscle tone. None of the above methods of treatment, however, are very effective for periods in excess of a year.
Overflow incontinence is caused by anatomical obstructions in the bladder or underactive detrustors. It is characterized by a distended bladder which leads to frequent urine leakage. This type of incontinence is treated acutely by catheterization and long-term by drug therapy. Enuresis or bed-wetting is a problem in pediatrics and is controlled by various alarming devices and pads with sensors. Enuresis is not considered a serious problem unless it lasts beyond the age of four or five. Finally, there is true functional incontinence which occurs in patients with chronic impairment either of mobility or mental function. Such patients are usually treated by the use of diapers, incontinence pads or continuous catheterization (BBI, 1985 Report 7062).
It is therefore an object of the present invention to provide a method and material for treating vesicouretal reflux which results in a natural and permanent cure to the defect.
It is a further object of the present invention to provide a method and material for treating vesicouretal reflux which is quick, simple, safe, and relatively non-invasive.
It is another object of the present invention to provide a bulking material which is non-biodegradable, biocompatible, non-migratory, and can be injected.